Project Summary: Early abstinence from methamphetamine (MA) is associated with mood and socio-emotional disturbances, including depression and anxiety, but also irritability, problems controlling anger, and a tendency to engage in violent and aggressive behavior. The proposed research will investigate whether deficits in emotion regulation and associated neural circuitry contribute to these behaviors. The studies will test the structural and functional integrity of a neural circuit that includes prefrontal cortex (PFC) and the amygdala in healthy and MA-dependent individuals (abstinent 4-7 days), using functional MRI with a task that involves threatening faces to assess emotion regulation, and diffusion tensor imaging (DTI) to assess white matter integrity. Studies will also assess impulsively aggressive behavior, using self-report scales and a probe task of aggression, and relate measures of aggressiveness to the capacity for emotion regulation and associated brain function/connectivity. Individuals who show difficulty regulating emotion and/or show poor white matter integrity are expected to exhibit higher levels of aggression. Both aims will take into account the potentially influential effects of sex, which can affect brain function/structure and behavior, in particular violent and aggressive impulses. The goal of this research is to form a more thorough understanding of the symptoms associated with early abstinence from MA, as this is a time during which MA-dependent individuals are particularly vulnerable to relapse. Understanding the neural deficits that characterize this period, as well as their relationship to behavioral problems, is crucial for identifying targets for intervention. Identification of specific targets, and the subsequent potential for development of appropriate approaches to address them, could lead to improved treatment retention, relapse prevention, and general well-being of individuals affected by substance abuse disorders. PUBLIC HEALTH RELEVANCE: Methamphetamine (MA) abuse is a major medical, social, and legal concern, and violent and aggressive behaviors associated with MA abuse tax public safety, as well as the health care and legal systems. However, no consistently effective treatment is available, and existing approaches have had limited success. A better understanding of the behavioral and neurobiological deficits associated with early abstinence from MA could prove beneficial for the development of treatments, and help improve quality of life not only for individuals with substance abuse disorders, but also individuals affected by their behavior.